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US 2026/0242373 A1Published application
Nbd1 modulators and methods of using the same
AssigneesSionna Therapeutics Inc., Genzyme Corporation
InventorsJunkai Liao, Mark Munson, Sukanthini Thurairatnam, Bradford Hirth, Zhongli Gao, Gregory Donald Hurlbut, Jinyu Liu, Michael Kothe, George Topalov, John E. Macor, Yi Li, Andrew Good, David Borcherding
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Abstract
The present disclosure includes, among other things, CFTR modulators, pharmaceutical compositions, and methods of making and using the same.
Claims137
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof
- wherein
- W1 is selected from the group consisting of —C(H)═, and —N═;
- W2 is selected from the group consisting of —C(H)═, —C(Rd)═, and —N═;
- W3 is selected from the group consisting of —C(H)═, —C(Rd)═, and —N═;
- W4 is selected from the group consisting of —C(H)═, —C(Rd4)═, and —N═;
- W5 is selected from the group consisting of —C(H)═, —C(Rd5)═, and —N═;
- W6 is selected from the group consisting of —C(H)═, —C(R′)═, and —N═;
- W7 is selected from the group consisting of —C(H)═, —C(Rc)═, and —N═;
- W8 is selected from the group consisting of —C(H)═, —C(Rc)═, and —N═;
- W9 is selected from the group consisting of —C(H)═, —C(Rc9)═, and —N═;
- Ring A is optionally substituted 5-membered heteroaryl, containing 1-2 heteroatoms selected from N, S, and O;
- Ring B is optionally substituted 5-membered heteroaryl containing up to three heteroatoms selected from N, S, and O;
- each Ra is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R′)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Ra is independently substituted with 0-4 instances of Raa,
- each Raa is independently selected from the group consisting of halogen, —COOH, —CN, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-7 membered heterocyclyl, —OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, and —N(H)C(O)N(R1)2,
- wherein two instances of Raa are optionally taken together with any intervening atoms to form an optionally substituted 4-6 membered carbocyclyl or optionally substituted 4-6 membered heterocyclyl ring;
- each Rb is independently selected from the group consisting of halogen, oxo, —CN, —NO2—OR1, —SR1, —N(R′)2, —C(O)OR1, C(O)N(R′)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl,
- wherein two instances of Rb are optionally taken together with any intervening atoms to form an optionally substituted 5-6 membered carbocyclyl or optionally substituted 5-6 membered heterocyclyl ring;
- each Rc is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R′)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- each Rd is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —SO(NR2)R1, —SO2N(R2)R1, —N(H)C(O)N(R′)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- Rc9 is halogen;
- Rd4 is halogen;
- Rd5 is halogen;
- each R1 is independently selected from the group consisting of hydrogen, —(CH2)1-3R2, —C(O)R2, —(CH2)1-3OR2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- wherein two instances of R1 are optionally taken together with any intervening atoms to form an optionally substituted 3-7 membered heterocyclyl ring;
- each R2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- each R3 is independently selected from the group consisting of hydrogen, unsubstituted alkyl or haloalkyl
- X is selected from the group consisting of —O—, —S—, —S(O)—, —S(O)2—, —C(R1)(R2)—, —C(O)—, and —CH(OH)—;
- Y is selected from the group consisting of optionally substituted C1-C3 alkylene, —O—, —S—, —S(O)—, —SO2N(R2)—, and —S(O)2—;
- n is 0, 1, 2, or 3;
- m is 1, 2, or 3,
- wherein the compound is not
29 more elements
A compound of Formula (II):
- or a pharmaceutically acceptable salt thereof wherein
- W1 is selected from the group consisting of —C(Rd)═, and —N═;
- W2 is selected from the group consisting of —C(H)═, —C(Rd)═, and —N═;
- W3 is selected from the group consisting of —C(Rd3)═, and —N═;
- W4 is selected from the group consisting of —C(Rd4)═, and —N═;
- W5 is selected from the group consisting of —C(H)═, —C(Rd5)═, and —N═;
- W6 is selected from the group consisting of —C(H)═, —C(Re)═, and —N═;
- W7 is selected from the group consisting of —C(H)═, —C(Re)═, and —N═;
- W8 is selected from the group consisting of —C(H)═, —C(Re)═, and —N═;
- W9 is selected from the group consisting of —C(H)═, —C(Re9)═, and —N═;
- Ring A is optionally substituted phenyl or optionally substituted 6-membered heteroaryl, containing 1-2 nitrogen atoms;
- Ring B is optionally substituted 5-membered heteroaryl containing up to three heteroatoms selected from N, S, and O;
- each Ra is selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Ra is independently substituted with 0-4 instances of Raa;
- each Raa is independently selected from the group consisting of halogen, —COOH, —CN, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-7 membered heterocyclyl, —OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, and —N(H)C(O)N(R1)2,
- wherein two instances of Raa are optionally taken together with any intervening atoms to form an optionally substituted 4-6 membered carbocyclyl or optionally substituted 5-6 membered heterocyclyl ring;
- each Rb is independently selected from the group consisting of halogen, oxo, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- each Rc is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- each Rd is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —SOR1, —SO2N(R2)R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- Rc9 is halogen;
- Rd3 is hydrogen or Rd;
- Rd4 is hydrogen or halogen;
- wherein when Rd4 is fluoro, Rd3 is not hydrogen, fluoro, chloro, methyl, cyclopropyl, —CH2CF3, —CH2CHF2, —(CH2)0-3SO2R1, —(CH2)0-3SOR1, —(CH2)0-3P(O)Me2, —SR1, thiazolyl, pyrazolyl, or (CH2)0-3 (3-7 membered heterocyclyl);
- wherein when Rd4 is hydrogen, Rd3 is not hydrogen, methyl, —CH2OH, —CH2NH(tBu), or —C(O)NHMe;
- Rd5 is halogen;
- each R1 is independently selected from the group consisting of hydrogen, —(CH2)1-3R2, —C(O)R2, —(CH2)1-3OR2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- wherein two instances of R1 are optionally taken together with any intervening atoms to form an optionally substituted 3-7 membered heterocyclyl ring;
- each R2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl,
- optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- each R4 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Ra is independently substituted with 0-4 instances of Raa,
- Y is selected from the group consisting of optionally substituted C1-C3 alkylene, optionally substituted C3-C7 cycloalkylene, optionally substituted 3-7 membered heterocyclylene, —O—, —S—, —S(O)—, —S(O)N(R4)—, —SO2N(R2)—, and —S(O)2—;
- n is 0 or 1.
- m is 1, 2, or 3.
29 more elements
A compound of Formula (III):
- or a pharmaceutically acceptable salt thereof wherein
- W1 is selected from the group consisting of —C(H)═, and —N═;
- W2 is selected from the group consisting of —C(H)═, —C(Rd)═, and —N═;
- W3 is selected from the group consisting of —C(H)═, —C(Rd)═, and —N═;
- W4 is selected from the group consisting of —C(H)═, —C(Rd4)═, and —N═;
- W5 is selected from the group consisting of —C(H)═, —C(Rd5)═, and —N═;
- W6 is selected from the group consisting of —C(H)═, —C(Rc)═, and —N═;
- W7 is selected from the group consisting of —C(H)═, —C(Rc)═, and —N═;
- W8 is selected from the group consisting of —C(H)═, —C(Rc)═, and —N═;
- W9 is selected from the group consisting of —C(H)═, —C(Rc9)═, and —N═;
- Ring A is optionally substituted phenyl or optionally substituted 6-membered heteroaryl, containing 1-2 nitrogen atoms;
- each Ra is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Ra is independently substituted with 0-4 instances of Raa;
- each Raa is independently selected from the group consisting of halogen, —COOH, —CN, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-7 membered heterocyclyl, —OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, and —N(H)C(O)N(R1)2,
- wherein two instances of Raa are optionally taken together with any intervening atoms to form an optionally substituted 4-6 membered carbocyclyl or heterocyclyl ring;
- each Rb is independently selected from the group consisting of halogen, oxo, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- each Rc is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- each Rd is independently selected from the group consisting of halogen, —CN, —NO2—OR1, —SR1, —N(R1)2, —C(O)OR1, C(O)N(R1)2, —N(H)C(O)R1, —SO2R1, —SO(NR2)R1, —SO2N(R2)R1, —N(H)C(O)N(R1)2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- Rc9 is halogen;
- Rd5 is halogen;
- Rd5 is halogen;
- each R1 is independently selected from the group consisting of hydrogen, —(CH2)1-3R2, —C(O)R2, —(CH2)1-3OR2, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- wherein two instances of R1 are optionally taken together with any intervening atoms to form an optionally substituted 3-7 membered heterocyclyl ring;
- each R2 is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;
- X is selected from the group consisting of optionally substituted C1-C3 alkylene, C═O, —S—, —S(O)—, —SO(NR2)—, and —S(O)2—;
- Y is optionally substituted C1-C3 alkylene optionally substituted C3-C7 cycloalkylene, or optionally substituted 3-7 membered heterocyclylene;
- p is 0, 1, or 2;
- n is 0, or 1;
- mis 1, 2, or 3.
25 more elements
The compound of claim 125, wherein Ras is fluoro.
A compound selected from the group consisting of
- Com-
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- or a pharmaceutically acceptable salt thereof.
61 more elements
A pharmaceutical composition comprising a compound of any of the previous claims and a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.